Sexual function in young women with spontaneous 46,XX primary ovarian insufficiency.

OBJECTIVE: To assess sexual function in women with spontaneous 46,XX primary ovarian insufficiency after at least 3 months of a standardized hormone replacement regimen. DESIGN: Cross-sectional cohort, controlled. SETTING: National Institutes of Health Clinical Research Center. PATIENT(S): Women with primary ovarian insufficiency (n = 143) and regularly menstruating controls (n = 70). INTERVENTION(S): Self-administered questionnaires, 100 microg/day E(2) patch, oral medroxyprogesterone acetate 10 mg for 12 days each month for patients. MAIN OUTCOME MEASURE(S): Derogatis Interview for Sexual Function Self-Report (DISF-SR). RESULT(S): Women with primary ovarian insufficiency had significantly lower DISF-SR composite scores compared with control women. Their serum total testosterone levels were significantly correlated with DISF-SR composite score, although this accounted for only 4% of the variance in this measure. Patients with testosterone levels below normal tended to have lower DISF-SR composite scores. Of patients with primary ovarian insufficiency, 9 of 127 (7%) scored below the second percentile on the composite sexual function score, compared with 1 of 49 control women (2%). CONCLUSION(S): As assessed by the DISF-SR, sexual function is in the normal range for most young women with 46,XX spontaneous primary ovarian insufficiency who are receiving physiologic E(2) replacement. However, as a group, these young women score significantly lower on this sexual function scale than control women.

The FMR1 premutation and reproduction.

OBJECTIVE: To update clinicians on the reproductive implications of premutations in FMR1 (fragile X mental retardation 1). Fragile X syndrome, a cause of mental retardation and autism, is due to a full mutation (>200 CGG repeats). Initially, individuals who carried the premutation (defined as more than 55 but less than 200 CGG repeats) were not considered at risk for any clinical disorders. It is now recognized that this was incorrect, specifically with respect to female reproduction. DESIGN AND SETTING: Literature review and consensus building at two multidisciplinary scientific workshops. CONCLUSION(S): Convincing evidence now relates the FMR1 premutation to altered ovarian function and loss of fertility. An FMR1 mRNA gain-of-function toxicity may underlie this altered ovarian function. There are major gaps in knowledge regarding the natural history of the altered ovarian function in women who carry the FMR1 premutation, making counseling about reproductive plans a challenge. Women with premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Specialists in reproductive medicine can provide a supportive environment in which to explain the implications of FMR1 premutation testing, facilitate access to testing, and make appropriate referral to genetic counselors.

Testosterone deficiency in young women with 46,XX spontaneous premature ovarian failure.

OBJECTIVE: To determine whether women with 46,XX spontaneous premature ovarian failure have lower serum free-T levels than do control women. DESIGN: Cross-sectional. SETTING: National Institutes of Health Clinical Research Center. PATIENT(S): Women with 46,XX spontaneous premature ovarian failure (n = 130). INTERVENTION(S): Evaluation while off any estrogen therapy and then again after receiving a standardized hormone regimen. Regularly menstruating control women (n = 65) were sampled during the midfollicular phase. MAIN OUTCOME MEASURE(S): Serum total T by RIA after extraction and column chromatography, free T by equilibrium dialysis, and sex hormone-binding globulin by immunoradiometric assay. RESULT(S): While off estrogen therapy patients had a median serum free-T concentration that was statistically significantly lower than controls (2.2 vs. 3.3 pg/mL). This dropped significantly lower to 1.9 pg/mL while the patients were on physiologic transdermal E(2) therapy. This is despite the fact that sex hormone-binding globulin levels did not change. While on E(2) therapy, 13% of women (95% confidence interval, 7.9%-20.3%) had serum free-T levels below the lower limit of normal (<1.1 pg/mL). CONCLUSION(S): As a group, young women with 46,XX spontaneous premature ovarian failure have reduced circulating free-T levels, both during an interval off of estrogen therapy and while on physiologic transdermal E(2) therapy.

Effects of ovarian failure and X-chromosome deletion on body composition and insulin sensitivity in young women.

OBJECTIVE: Menopause is associated with increased visceral adiposity and reduced insulin sensitivity. It remains unclear whether these changes are due primarily to ovarian failure or aging. The aim of this study was to clarify the impact of ovarian failure on body composition and insulin sensitivity in young women. DESIGN: In a cross-sectional study, we compared main outcome measures (body mass index, body composition by dual-energy x-ray absorptiometry, and insulin sensitivity by Quantitative Insulin Sensitivity Check Index) in three groups: women with 46,XX premature ovarian failure (POF), women with premature ovarian failure associated with 45,X or Turner syndrome (TS), and normal control women (NC). Participants were enrolled in National Institutes of Health Clinical Center protocols between years 2000 and 2005. RESULTS: Mean body mass index (+/- SD) was lower in women with POF (n = 398): 24.3 +/- 5 kg/m versus 27.8 +/- 7 for women with TS (n = 131) and 26.6 +/- 4 for controls (n = 73) (both P < 0.001). Only 33% of women with POF were overweight or obese, compared with 56% of those with TS and 67% of NC women (P < 0.0001 for both). Despite less obesity, women with POF had lower insulin sensitivity (0.367 +/- 0.03) compared with those with TS (0.378 +/- 0.03, P = 0.003) and NC women (0.376 +/- 0.03, P = 0.04). In groups selected for similar age and body mass index, women with POF (n = 89), women with TS (n = 48), and NC women (n = 40) had similar total body and trunk adiposity. After adjustment for age and truncal adiposity, women with POF had significantly lower insulin sensitivity than women with TS (P = 0.03) and NC women (P = 0.049). CONCLUSIONS: In contrast to observations in middle-aged postmenopausal women, ovarian failure in young women is not associated with increased total or central adiposity. In fact, women with TS were similar to NC women, whereas women with POF were leaner. The lower insulin sensitivity observed in women with POF deserves further investigation.

A woman with spontaneous premature ovarian failure gives birth to a child with fragile X syndrome.

OBJECTIVE: To inform clinicians about a reproductive risk associated with spontaneous premature ovarian failure and the fragile X mental retardation 1 gene (FMR1). DESIGN: Case report. SETTING: National Institutes of Health Clinical Center. PATIENT(S): A 35-year-old woman with confirmed spontaneous premature ovarian failure. INTERVENTION(S): FMR1 genetic testing. MAIN OUTCOME MEASURE(S): Number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. RESULT(S): Despite having ovarian failure the woman subsequently conceived and delivered a son with fragile X syndrome (>200 CGG repeats). She was then found to carry an FMR1 premutation (85 CGG repeats). CONCLUSION(S): This is a real-life manifestation of a theoretical risk; a woman conceived subsequent to the diagnosis of spontaneous premature ovarian failure and has a child who manifests mental retardation due to fragile X syndrome. Women with spontaneous premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Should an FMR1 premutation be uncovered, this will allow patients to make informed reproductive decisions and help clinicians to properly diagnose family members who may have menstrual irregularity, developmental delay, or neurologic symptoms.